Fig. 4.

Timeline of events following expression of K-Ras. The time axis depicts the various events after stimulation of the K-RAS gene expression. The findings of Huang et al. indicate that mitochondria-linked changes are observed around the time of the increase in the K-Ras protein (142). This is then followed by other changes, such as alteration in cell metabolism. Gene mutations would form as a downstream epiphenomenon of altered metabolism. Malignant transformation, documented by the colony-forming activity of the cells and their propensity to form tumors ensue much later. According to these findings, the Warburg effect (aerobic fermentation) arises as a consequence of K-RAS-induced respiratory injury. This timeline is in general agreement with Warburg’s central theory and with other similar findings that respiratory disturbance is an initial event in K-RAS-induced tumorigenesis (237–239). The timeline will be greatly protracted in vivo as shown from the Roskelley et al. (240) experiments. Reprinted from Neuzil et al. (143) with permission.